Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors
Copyright policy )Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors
We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9 nM) was identified following this approach.
- Novartis Institutes for BioMedical Research Switzerland
- Novartis (Switzerland) Switzerland
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Crystallography, X-Ray, Receptor, IGF Type 1, Structure-Activity Relationship, Pyrimidines, Microsomes, Liver, Humans, Pyrroles, Protein Kinase Inhibitors
Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Crystallography, X-Ray, Receptor, IGF Type 1, Structure-Activity Relationship, Pyrimidines, Microsomes, Liver, Humans, Pyrroles, Protein Kinase Inhibitors
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